Human mast cells (MC) originate from pluripotential progenitor cells and migrate as immature cells from the bone marrow to tissue sites including the skin, lung and gastrointestinal tract. Once there, these precursors mature and participate in both innate and acquired immune responses by the production of cytokines and other inflammatory mediators. In our efforts to better understand the role of mast cells in innate immunity, HIV infected mast cells were recently examined. It was observed that FcRI-bound IgE (IgE-FcRI), or aggregated IgE-FcRI significantly enhanced progenitor mast cell expression of CXCR4 and their susceptibility to X4 and R5X4 virus within a unique developmental period during mast cell ontogeny. Furthermore, IgE-FcRI aggregation mediated by superallergens, such as HIVgp120 or soluble Schistosoma mansoni egg Ag (SmEA), also enhances susceptibility of progenitor MCs to X4 and R5X4 virus. These findings indicate that IgE may significantly influence the overall fitness advantage for X4 and R5X4 virus in the MC reservoir of persistent HIV infection. The clinical implications of these findings are that HIV-positive individuals with pre-existing comorbid conditions associated with elevated IgE levels, such as atopic disease or helminthic infections, may have increased risk for infection with X4- and R5X4-HIV. Mast cell regulation is critical to the development of an appropriate immune response. We observed that CD72 is expressed on human mast cells and functions as a mast cell inhibitory receptor. The concurrent ligation of CD72 and KIT resulted in an increase in the phosphorylation of CD72, and enhanced association between CD72 and SHP-1. This led to the suppression of the KIT-mediated phosphorylation of SFKs and ERKs, critical players in KIT-mediated human mast cell responses. Thus, ligation of CD72 reduced KIT-mediated proliferation, chemotaxis, and MCP-1 (CCL2) production in human MCs and the suppression of growth of HMC1.2 cells harboring the gain-of-function mutation in the KIT gene. From these studies, we conclude that CD72/CD100 interactions downregulate KIT-mediated mast cell responses via the formation of the CD72/SHP-1 complex. Thus, downregulation of KIT-mediated responses through CD72 may provide a potential means for the control of mast cell-driven disorders.